Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1–8 mg/kg), the benzodiazepine diazepam (1 mg/kg), the cannabinoid CB1 receptor antagonist rimonabant (1 mg/kg), or JZL184 (8 mg/kg) coadministered with rimonabant (1 mg/kg). JZL184 (8 mg/kg) produced anxiolytic-like effects (i.e. increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB1. Anxiolytic effects of JZL184 were preserved following chronic (8 mg/kg per day × 6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5 mg/kg i.p.) 24 or 72 h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.

Exosomes are served as substitutes for stem cell therapy, playing important roles in mediating heart repair during myocardial infarction injury. Evidence have indicated that lipopolysaccharide (LPS) pre‐conditioning bone marrow‐derived mesenchymal stem cells (BMSCs) and their secreted exosomes promote macrophage polarization and tissue repair in several inflammation diseases; however, it has not been fully elucidated in myocardial infarction (MI). This study aimed to investigate whether LPS‐primed BMSC‐derived exosomes could mediate inflammation and myocardial injury via macrophage polarization after MI. Here, we found that exosomes derived from BMSCs, in both Exo and L‐Exo groups, increased M2 macrophage polarization and decreased M1 macrophage polarization under LPS stimulation, which strongly depressed LPS‐dependent NF‐κB signalling pathway and partly activated the AKT1/AKT2 signalling pathway. Compared with Exo, L‐Exo had superior therapeutic effects on polarizing M2 macrophage in vitro and attenuated the post‐infarction inflammation and cardiomyocyte apoptosis by mediating macrophage polarization in mice MI model. Consequently, we have confidence in the perspective that low concentration of LPS pre‐conditioning BMSC‐derived exosomes may develop into a promising cell‐free treatment strategy for clinical treatment of MI.

NIR-II fluorophores have shown great promise for biomedical applications with superior in vivo optical properties. To date, few small-molecule NIR-II fluorophores have been discovered with donor-acceptor-donor (D-A-D) or symmetrical structures, and upconversion-mitochondria-targeted NIR-II dyes have not been reported. Herein, we report development of D-A type thiopyrylium-based NIR-II fluorophores with frequency upconversion luminescence (FUCL) at ~580 nm upon excitation at ~850 nm. H4-PEG-PT can not only quickly and effectively image mitochondria in live or fixed osteosarcoma cells with subcellular resolution at 1 nM, but also efficiently convert optical energy into heat, achieving mitochondria-targeted photothermal cancer therapy without ROS effects. H4-PEG-PT has been further evaluated in vivo and exhibited strong tumor uptake, specific NIR-II signals with high spatial and temporal resolution, and remarkable NIR-II image-guided photothermal therapy. This report presents the first D-A type thiopyrylium NIR-II theranostics for synchronous upconversion-mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and excellent photothermal efficiency.

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Novel NIR-II organic fluorophores were designed and synthesized using an AIE and highly twisted donor–acceptor distortion strategy for bio-imaging beyond 1550 nm.

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Cardiovascular disease is a major cause of death worldwide. Inflammasome infiltration has been identified to play a central role in the pathological progression of certain cardiovascular diseases, such as vascular damage spanning atherosclerosis, aneurysm, or arteritis; ischemic heart disease; and other nonischemic heart diseases including diabetic cardiomyopathy, chronic heart failure, and hypertension- or virus-induced cardiac dysfunction. The NLRP3 inflammasome, a key participant in the innate immune response, requires both priming and activation signals for the initiation of inflammation. Piling evidence has revealed that the NLRP3 inflammasome could exert an inflammatory effect by inducing the secretion of proinflammatory cytokines (i.e., IL-1β, IL-18) or could cause pyroptosis, a novel programmed cell death process, in a caspase-1-dependent manner. The importance of the NLRP3 inflammasome in cardiac disease has been broadly investigated. In this review, we present the current knowledge regarding the function of NLRP in vascular disease, ischemic heart disease, and nonischemic heart disease and discuss the potential therapeutic options targeting the NLRP3 inflammasome.

Summary A fundamental aspect of episodic memory is that retrieval of information can occur when encoding is incidental and memory assessment is unexpected [1–4]. These features are difficult to model in animals because behavioral training likely gives rise to well-learned expectations about the sequence of events. Thus, the possibility remains that animals may solve an episodic-memory test by using well-learned semantic rules without remembering the episode at memory assessment. Here we show that rats can answer an unexpected question after incidental encoding in a hippocampal-dependent manner, consistent with the use of episodic memory. Rats were initially trained to report about a recent event (food vs. no-food) and separately searched for food where there was no expectation of being asked about the presence of food. To test episodic memory, rats were given the opportunity to incidentally encode the presence or absence of food and were unexpectedly asked to report about the recent event. Temporary inactivation of the CA3 region of the hippocampus with bilateral infusions of lidocaine selectively eliminated the ability of rats to answer the unexpected, but not the expected, question. Our studies suggest that rats remember an earlier episode after incidental encoding based upon hippocampal-dependent episodic memory.